2. Academic Validation
  3. Water molecules in the cannabinoid receptor 2 binding site crucially impact the discovery of novel ligands

Water molecules in the cannabinoid receptor 2 binding site crucially impact the discovery of novel ligands

  • Eur J Med Chem. 2025 Dec 5:299:117846. doi: 10.1016/j.ejmech.2025.117846.
Magdalena M Scharf 1,  Morgan Scott-Dennis 2,  Leire Borrega-Roman 2,  Franziska N Z Giese 1,  Darya Plevako 2,  David A Sykes 2,  Dmitry B Veprintsev 3,  Peter Kolb 4
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Chemistry, University of Marburg, Marburg, Germany.
  • 2 Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK.
  • 3 Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK. Electronic address: dmitry.veprintsev@nottingham.ac.uk.
  • 4 Institute of Pharmaceutical Chemistry, University of Marburg, Marburg, Germany. Electronic address: peter.kolb@uni-marburg.de.
PMID: 40812071 DOI: 10.1016/j.ejmech.2025.117846
Abstract

The Cannabinoid Receptor 2 (CB2R) is of considerable therapeutic and scientific interest. Hence, the discovery of novel molecules that target and modulate this receptor, ideally selectively over its closest relative, the Cannabinoid Receptor 1, is of great importance. In this study, we aimed to discover novel ligands targeting the CB2R using large library in silico docking screens. However, since the CB2R binding site is difficult to target with in silico methods due to its hydrophobic nature, we used a variety of screening approaches, including the placement of water molecules in predicted water sites of the receptor binding site, and screening against multiple docking setups and receptor conformations. We systematically evaluated these different approaches to support future screens at the CB2R and Other receptors. In the present work, each setup contributed different ligands of varying intrinsic activities, leading to an overall improved hit rate compared to that of a single screen. Of the novel ligands of the CB2R discovered and experimentally confirmed in this study, one series features high-affinity ligands with a previously undescribed scaffold.

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